Neurofibromatosis type-2 (NF2) is a dominantly inherited genetic disorder characterized by the formation of benign, slow growing tumors of the central nervous system. The NF2 tumor suppressor gene encodes a novel member of the 4.1 superfamily called Merlin. Proteins of the 4.1 superfamily are generally believed to organize function domains within the plasma membrane by linking transmembrane proteins with the underlying cytoskeleton or cytosolic effectors. While the identification of Merlin as a member of the protein 4.1 superfamily has been of great interest, it has not led to a specific hypothesis regarding its cellular function or its role in tumor suppression. During the past two years, I have characterized the Merlin protein using a combination of genetic and molecular approaches, thereby defining functional regions within the protein. In addition, I have initiated a genetic screen to identify genes that interact genetically with a dominant negative form of Merlin that I have engineered. The goal for the last year of this investigation will be to clone and characterize several novel loci that are involved in Merlin based regulation of proliferation.